1. Field of the Invention
This invention relates to medicinal compositions comprising a serotonin precursor such as L-tryptophan and a serotonin-specific reuptake inhibitor such as trazodone. The compositions are useful in controlling pain, sedation, and depression in animals. This invention further relates to a method of controlling pain, depression and sedation in animals which comprises administering the medicinal compositions of this invention or components thereof internally. The invention also relates to the method of coadministering the compositions of this invention or components thereof with narcotics to achieve potentiation of the analgesic effect of the narcotic.
2. Description of the Background Art
The use of narcotics is widespread for the control of chronic pain such as that sometimes encountered in advanced disease states of cancer patients. However, long term use of narcotics is met with increasing tolerance in most patients, requiring increased dosages and more frequent administration to achieve a reasonable comfort level. The opiate effects thereof produce a depressant effect which limits dosages and interrupts normal sleep patterns with long term use. Additionally, it frequently becomes impossible to ease the patient's pain to any reasonable degree.
In addition to the opiate effects, it is known that there is a transient increase in brain serotonin levels following administration of a narcotic, i.e., (at an interval of approximately thirty minutes). This increase in brain serotonin levels produced by the administered narcotics produces an analgesic effect. Serotonin is a known calmative neurotransmitter and produces a certain degree of sedation as well.
Serotonin (5-hydroxytryptamine or 5-HT) is present in highest concentration in blood platelets and in the gastrointestinal tract, where it is found in the enterochromaffin cells and the myenteric plexis. Lesser amounts are found in the brain, particularly in the hypothalamus.
Serotonin is found in relatively high concentrations in the lateral gray horns of the spinal cord and in a number of areas in the brain. It can be shown that there is a system of serotonin-containing neurons that have their cell bodies in the raphe nuclei of the brain stem and project to portions of the hypothalamus, the limbic system, the neocortex, and the spinal cord.
Serotonin is formed in the body by hydroxylation and decarboxylation of the essential amino acid L-tryptophan. In the biosynthesis of serotonin from L-tryptophan, L-tryptophan is hydroxylated in the presence of the enzyme tryptophan hydroxylase to form the intermediate product L-5-hydroxytryptophan (L-5-HTP). This intermediate product is decarboxylated in the presence of the enzyme 5-hydroxytryptophan decarboxylase to form serotonin.
After release from serotonergic neurons, much of the released amine is recaptured by an active reuptake mechanism. Additionally, serotonin is inactivated by monoamine oxidase to form 5-hydroxyindoleacetic acid (5-HIAA). 5-HIAA is the principal urinary metabolite of serotonin. For a more complete description of the biosynthesis and metabolism of serotonin, see Gnong, W. F., Review of Medicinal Physiology, pages 190-191 (1979) and Harrison's PRINCIPALS OF INTERNAL MEDICINE, 10th Edition, edited by Petersdorf, R. G. et al., page 827 (1983).
It is also known that ascorbic acid (vitamin C) plays an active role in the hydroxylation of L-tryptophan to L-5-HTP. See CLINICAL GUIDE TO PARENTERAL MICRONUTRITION, Edited by Thomas Baumgartner, Educational Publications, Melrose Park, Ill., page 276 (1984). Further, in the biosynthetic pathway from L-5-HTP to serotonin by decarboxylation of the L-5-HTP, pyridoxine (vitamin B6) plays an integral role. See, CLINICAL GUIDE TO PARENTERAL MICRONUTRITION, Edited by Thomas Baumgartner, Educational Publications, Melrose Park, Ill. page 298 (1984). L-tryptophan or its precursor, L-5-HTP, and pharmaceutically acceptable salts thereof are well known for the treatment of various diseases in animals. U.S. Pat. No. 3,795,739 to Birkmayer et al. discloses pharmaceutical compositions for treating Parkinson's disease, said compositions containing L-dopa or a pharmaceutically acceptable salt thereof in mixture with L-tryptophan, L-5-HTP, or pharmaceutically acceptable salts thereof. U.S. Pat. No. 4,161,530 to Coella discloses pharmaceutical compositions useful as hypnotics comprising a pharmacologically active beta receptor-blocking compound and L-tryptophan. U.S. Pat. No. 4,397,866 to Wurtman discloses the administration of L-tryptophan to treat medical conditions where there is a need to sustain or increase brain serotonin levels.
Trazodone, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridi n-3(2H)-one) is described in the Merck Index, 9th Edition, 9266 (1976) as a tranquilizer and hypotensive. U.S. Pat. No. 3,381,009 to Palazzo et al. further describes a family of pyridine derivatives including trazodone as having tranquilizing, hypotensive, and analgesic activity.
U.S. Pat. No. 4,444,778 to Coughlin describes a method for improving the arteriosclerotic condition in an animal comprising administering serotonin regulating agents which will reduce the amount of serotonin in the blood vessels, optionally in combination with a tryptophan-poor diet, in order to interfere with the signal for smooth muscle cell proliferation. Among the compounds disclosed for use as a serotonin receptor blocker is trazodone. According to Coughlin, this serotonin receptor blocker operates by inhibiting the proliferation action of serotonin on smooth muscle cells, limiting the ability of platelet-released serotonin to stimulate smooth muscle cell proliferation.
U.S. Pat. No. 4,131,675 to Sylvestrini discloses the use of combinations of L-dopa with trazodone in Parkinsonism in order to avoid the side effects of L-dopa resulting from stimulation of the adrenergic system. Trazodone is further described as having adrenolytic effects.
U.S. Pat. No. 4,329,356 to Holland describes the use of fluoxetine (N-methyl-3-(p-trifluoromethylphenoxyl)-3-phenylpropylamine) in combination with L-5-HTP for the treatment of hypertension. The fluoxetine is described as a specific inhibitor of the serotonin neuron pump, i.e., as a serotonin "uptake" inhibitor.
However, a medicament comprising the combination of a serotonin precursor and trazodone, said medicament useful for the treatment of pain, depression, or as a sedative, is not taught or suggested by the prior art.